Budesonide is a synthetic steroid with anti-inflammatory activity, used for preparing pharmaceutical compositions for the treatment of chronic and acute asthma of particular severity.
Budesonide and other structurally similar glucocorticoids were described for the first time in patent GB 1,429,922 in the name of the Bofors company.
Specifically, the budesonide compound was prepared in example 9 by reaction between 11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione, i.e. 16α-hydroxyprednisolone, and butyraldehyde in dioxane as solvent and perchloric acid as catalyst. At page 2, line 8 onwards, p-toluenesulphonic acid and hydrochloric acid as acid catalysts are also proposed, and a solvent equivalent to dioxane as the solvent. The solution, treated with methylene chloride, was then neutralized and the acetal formed was isolated by column chromatography purification on gel. According to the document, the final product is a mixture of stereoisomers which can be separated by gel filtration, for example as described in GB 1,428,416.
The budesonide compound is actually a mixture of two epimers, different for the spatial arrangement of the substituents at the carbon 22 atom of the dioxolane ring of the compound of formula (I). Specifically, the isomer with S configuration is commonly defined as epimer A, and the isomer with R configuration as epimer B (European Pharmacopeia 6.0, Budesonide, page 1342).
The currently employed synthesis for budesonide production, which enables an A/B epimer ratio of about 1/1 to be obtained, is still based on the reaction of 16α-hydroxyprednisolone (11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione) with butyraldehyde in dioxane, using perchloric acid as catalyst.
Although from the pharmacological viewpoint the R-epimer is the most active one, from the practical viewpoint, commercial authorization for budesonide can however only be obtained for specific epimeric ratios of R and S stereoisomers.
Document EP 875,516 in the name of Pharmabios then proposed a budesonide synthesis, enabling epimer distribution at position C-22 to be controlled, by reaction between 16α-hydroxyprednisolone and butyraldehyde in the presence of an aqueous hydrohalic acid chosen from hydrobromic acid and hydriodic acid, in which the hydrohalic acid is used both as solvent and catalyst. In the document, the use of hydrobromic acid (HBr) in aqueous solution is described as particularly advantageous, and considered as feature distinguishing from hydrochloric acid, due to the high solvent power of aqueous HBr which allows the acetylization to be conducted in the homogeneous phase thus controlling in a reliable way the ratio between the epimers.
Controlling the ratio between epimers A and B is therefore a problem related to the marketing of budesonide. Specifically, according to the European Pharmacopeia, the budesonide product must contain an epimer A percentage of between 40 and 51%, the remainder being epimer B; and, according to the US Pharmacopeia, the quantity of epimer A must be comprised between 44 and 51%. This percentage of epimer A is present in the crude reaction product of the methods currently used for budesonide production. Said methods however comprise a step of crystallization from methanol which, during the crystallizations, progressively reduces the quantity of epimer A as it is more soluble in methanol than epimer B.
This solubility difference between epimers A and B limits the number of crystallizations applicable to the crude product. There is therefore the problem of striking a balance between the desired purity requirement of the final product and the minimum quantity of epimer A demanded in the diastereoisomer mixture constituting budesonide.
An object of the present invention is therefore to obtain a quantity of epimer A directly from the condensation reaction such that even with the crystallizations needed to purify the product, an epimer A percentage quantity within the range from 44% to 51% is always achieved.
A further object of the invention is therefore to provide a final budesonide product that satisfies the requirements of both the EU Pharmacopeia and the US Pharmacopeia.